Combinations of genotoxic tests for the evaluation of group 1 IARC carcinogens

Bhagat, Jacky

doi:10.1002/jat.3496

Cited by 20 publications

(11 citation statements)

References 226 publications

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“…Intra-individual variation in DNA damage has been reported to be affected by age and reproductive status, although comparative data across organisms on the relationship between DNA damage, DNA repair, age and sex differences are lacking (Jha 2008). While published studies have demonstrated increased effects in human and mosquito fish ( Gambusia affinis ) females vs males in the micronucleus test (Caliani et al 2009; Fenech and Bonassi 2011), we did not find similar evidence in the literature for the comet assay; this is possibly because the micronucleus test detects a wider array of genotoxic effects (Bhagat 2018). In T. carolina , distinct levels of DNA damage between males and females were observed, with the females showing more damage, probably as a result of lower capacity of DNA repair than males.…”

Section: Discussioncontrasting

confidence: 88%

Application of the CometChip platform to assess DNA damage in field‐collected blood samples from turtles

Sýkora

Chiari

Heaton

et al. 2018

Environ and Mol Mutagen

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DNA damage has been linked to genomic instability and the progressive breakdown of cellular and organismal homeostasis, leading to the onset of disease and reduced longevity. Insults to DNA from endogenous sources include base deamination, base hydrolysis, base alkylation, and metabolism-induced oxidative damage that can lead to single-strand and double-strand DNA breaks. Alternatively, exposure to environmental pollutants, radiation or ultra-violet light, can also contribute to exogenously derived DNA damage. We previously validated a novel, high through-put approach to measure levels of DNA damage in cultured mammalian cells. This new CometChip Platform builds on the classical single cell gel electrophoresis or comet methodology used extensively in environmental toxicology and molecular biology. We asked whether the CometChip Platform could be used to measure DNA damage in samples derived from environmental field studies. To this end, we determined that nucleated erythrocytes from multiple species of turtle could be successfully evaluated in the CometChip Platform to quantify levels of DNA damage. In total, we compared levels of DNA damage in 40 animals from two species: the box turtle (Terrapene carolina) and the red-eared slider (Trachemys scripta elegans). Endogenous levels of DNA damage were identical between the two species, yet we did discover some sex-linked differences and changes in DNA damage accumulation. Based on these results, we confirm that the CometChip Platform allows for the measurement of DNA damage in a large number of samples quickly and accurately, and is particularly adaptable to environmental studies using field-collected samples. Environ. Mol. Mutagen. 59:322-333, 2018. © 2018 Wiley Periodicals, Inc.

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Section: Discussioncontrasting

confidence: 88%

Application of the CometChip platform to assess DNA damage in field‐collected blood samples from turtles

Sýkora

Chiari

Heaton

et al. 2018

Environ and Mol Mutagen

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“…Hence, we have demonstrated that a CometChip Platform pre-screen (single dose, acute treatment) may be used to identify DNA damaging agents, but not all genotoxicants will be detected using this method, based on mechanism of action. As recently described 63 , a thorough analysis of genotoxicants requires evaluation by a combination of tests (Comet/CometChip, Ames test, micronucleus, chromosomal aberration), each providing different mechanistic evaluations and revealing genotoxicity profiles based on different modes of action. We suggest that compounds that are negative in a CometChip Platform pre-screen should be subjected to more extensive testing that includes multiple doses and treatment times, in concert with additional assays (Ames test, micronucleus, chromosomal aberration).…”

Section: Discussionmentioning

confidence: 99%

Next generation high throughput DNA damage detection platform for genotoxic compound screening

Sýkora

Witt

Revanna

et al. 2018

Sci Rep

100

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Methods for quantifying DNA damage, as well as repair of that damage, in a high-throughput format are lacking. Single cell gel electrophoresis (SCGE; comet assay) is a widely-used method due to its technical simplicity and sensitivity, but the standard comet assay has limitations in reproducibility and throughput. We have advanced the SCGE assay by creating a 96-well hardware platform coupled with dedicated data processing software (CometChip Platform). Based on the original cometchip approach, the CometChip Platform increases capacity ~200 times over the traditional slide-based SCGE protocol, with excellent reproducibility. We tested this platform in several applications, demonstrating a broad range of potential uses including the routine identification of DNA damaging agents, using a 74-compound library provided by the National Toxicology Program. Additionally, we demonstrated how this tool can be used to evaluate human populations by analysis of peripheral blood mononuclear cells to characterize susceptibility to genotoxic exposures, with implications for epidemiological studies. In summary, we demonstrated a high level of reproducibility and quantitative capacity for the CometChip Platform, making it suitable for high-throughput screening to identify and characterize genotoxic agents in large compound libraries, as well as for human epidemiological studies of genetic diversity relating to DNA damage and repair.

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“…As mentioned above, no data from long-term carcinogenicity experiments with rodents are available at present. It is notable in this context that it was found that the sensitivity of a combination of positive MN assays with rodents and in vitro SCGE assays for the detection of group 1 carcinogens (IARC) was found to be 95.6% (Bhagat 2018). In regard to the MN data obtained in bone marrow cells, it will be relevant to investigate if the drugs induce alterations of the erythropoetic system (see above) and also if inhalative and oral exposure cause adverse effects.…”

Section: Discussionmentioning

confidence: 99%

Low doses of widely consumed cannabinoids (cannabidiol and cannabidivarin) cause DNA damage and chromosomal aberrations in human-derived cells

et al. 2018

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Cannabidiol (CBD) and cannabidivarin (CBDV) are natural cannabinoids which are consumed in increasing amounts worldwide in cannabis extracts, as they prevent epilepsy, anxiety, and seizures. It was claimed that they may be useful in cancer therapy and have anti-inflammatory properties. Adverse long-term effects of these drugs (induction of cancer and infertility) which are related to damage of the genetic material have not been investigated. Therefore, we studied their DNA-damaging properties in human-derived cell lines under conditions which reflect the exposure of consumers. Both compounds induced DNA damage in single cell gel electrophoresis (SCGE) experiments in a human liver cell line (HepG2) and in buccal-derived cells (TR146) at low levels (≥ 0.2 µM). Results of micronucleus (MN) cytome assays showed that the damage leads to formation of MNi which reflect chromosomal aberrations and leads to nuclear buds and bridges which are a consequence of gene amplifications and dicentric chromosomes. Additional experiments indicate that these effects are caused by oxidative base damage and that liver enzymes (S9) increase the genotoxic activity of both compounds. Our findings show that low concentrations of CBD and CBDV cause damage of the genetic material in human-derived cells. Furthermore, earlier studies showed that they cause chromosomal aberrations and MN in bone marrow of mice. Fixation of damage of the DNA in the form of chromosomal damage is generally considered to be essential in the multistep process of malignancy, therefore the currently available data are indicative for potential carcinogenic properties of the cannabinoids.Electronic supplementary materialThe online version of this article (10.1007/s00204-018-2322-9) contains supplementary material, which is available to authorized users.

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Combinations of genotoxic tests for the evaluation of group 1 IARC carcinogens

Cited by 20 publications

References 226 publications

Application of the CometChip platform to assess DNA damage in field‐collected blood samples from turtles

Application of the CometChip platform to assess DNA damage in field‐collected blood samples from turtles

Next generation high throughput DNA damage detection platform for genotoxic compound screening

Low doses of widely consumed cannabinoids (cannabidiol and cannabidivarin) cause DNA damage and chromosomal aberrations in human-derived cells

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